Fetal Urine Production Rate in Preterm Premature Rupture of Membranes Is Associated with Adverse Neonatal Outcome: A Pilot Study.
In this study, we evaluate the associations between fetal urinary production rate (FUPR), measured by ultrasound, and adverse neonatal outcome in women with preterm premature rupture of membranes (PPROM). We conducted a prospective pilot cohort of singleton pregnancies complicated by PPROM occurring at gestational week 24 or later managed until spontaneous labor (after 48 h of admission), chorioamnionitis, or induction by protocol at 35 + 0 weeks. FUPR was evaluated by 2D sonography at admission (corrected for gestational age). The main neonatal outcome measures were chorioamnionitis, placental inflammatory grading, first neonatal creatinine value, first neonatal dextrose value, length of neonatal intensive care unit (NICU) stay, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH) (grades I-IV), blood transfusions, reduced neonatal urine production rate (<4 mL/kg/h), and early neonatal sepsis. Samples of maternal (at admission) and umbilical cord blood were analyzed for interleukin-6 (IL-6) level. The study included 38 women. Low FUPR was associated with clinical chorioamnionitis, longer NICU hospitalization (p = 0.01), higher rates of NEC or IVH (p = 0.008), and blood transfusion (p = 0.004). A finding of FUPR on in utero ultrasound examination in pregnancies complicated by PPROM may be indicative of adverse neonatal outcome.


Workrelated risks and health problems of working children in urban Istanbul, Turkey.
The purpose of this cross-sectional study was to identify the work-related risks and health problems of working children. The sample included 167 working boys. These boys were chosen from schools giving occupational education in the industrial part of Istanbul. A questionnaire and worksite assessment checklists, developed by the researchers, were used as data gathering tools. Data were collected from the boys' schools and workplaces. From this data, it was found that 24.6% of the boys were jewelers, 32.3% were car mechanics and 43.1% were hairdressers. Findings revealed that 30.5% of the boys, who were engaged in child labor, were poor and dropped out of school to assist their families. Boys, whose mean age was 17.6 +/- 1.2, had been working since they were 13 yr old. The boys were also found to work 66.4 h a week, which was an unexpectedly high result considering the 35 hours limitation set by the laws of Turkey for working children. As for work-related risks, chemical risks for boys working as hairdressers (p<0.01), and using sharp tools and accidents for boys working as car mechanics were more common than the other groups (p<0.001, p<0.001). Boys working as hairdressers mostly had respiratory system problems, skin problems, and headache (p<0.001, p<0.001, p<0.001). Those working as car mechanics had nose/throat problems, and musculoskeletal system problems (p<0.001, p<0.01). Among those working as jewelers, eye-related problems were common (p<0.001). It was concluded from the findings of the present study that child labor creates an unhealthy environment for children.


Matrine prevents bone loss in ovariectomized mice by inhibiting RANKL-induced osteoclastogenesis.
Osteoporosis is a metabolic bone disease characterized by decreased bone density and strength due to excessive loss of bone protein and mineral content. The imbalance between osteogenesis by osteoblasts and osteoclastogenesis by osteoclasts contributes to the pathogenesis of postmenopausal osteoporosis. Estrogen withdrawal leads to increased levels of proinflammatory cytokines. Overactivated osteoclasts by inflammation play a vital role in the imbalance. Matrine is an alkaloid found in plants from the Sophora genus with various pharmacological effects, including anti-inflammatory activity. Here we demonstrate that matrine significantly prevented ovariectomy-induced bone loss and inhibited osteoclastogenesis in vivo with decreased serum levels of TRAcp5b, TNF-α, and IL-6. In vitro matrine significantly inhibited osteoclast differentiation induced by receptor activator for NF-κB ligand (RANKL) and M-CSF in bone marrow monocytes and RAW264.7 cells as demonstrated by tartrate-resistant acid phosphatase (TRAP) staining and actin-ring formation as well as bone resorption through pit formation assays. For molecular mechanisms, matrine abrogated RANKL-induced activation of NF-κB, AKT, and MAPK pathways and suppressed osteoclastogenesis-related marker expression, including matrix metalloproteinase 9, NFATc1, TRAP, C-Src, and cathepsin K. Our study demonstrates that matrine inhibits osteoclastogenesis through modulation of multiple pathways and that matrine is a promising agent in the treatment of osteoclast-related diseases such as osteoporosis.-Chen, X., Zhi, X., Pan, P., Cui, J., Cao, L., Weng, W., Zhou, Q., Wang, L., Zhai, X. Zhao, Q., Hu, H., Huang, B., Su, J. Matrine prevents bone loss in ovariectomized mice by inhibiting RANKL-induced osteoclastogenesis.


Endoplasmic Reticulum Stress and Ethanol Neurotoxicity.
Ethanol abuse affects virtually all organ systems and the central nervous system (CNS) is particularly vulnerable to excessive ethanol exposure. Ethanol exposure causes profound damages to both the adult and developing brain. Prenatal ethanol exposure induces fetal alcohol spectrum disorders (FASD) which is associated with mental retardation and other behavioral deficits. A number of potential mechanisms have been proposed for ethanol-induced brain damage; these include the promotion of neuroinflammation, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, and thiamine deficiency. The endoplasmic reticulum (ER) regulates posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress and induces unfolded protein response (UPR) which are mediated by three transmembrane ER signaling proteins: pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). UPR is initiated to protect cells from overwhelming ER protein loading. However, sustained ER stress may result in cell death. ER stress has been implied in various CNS injuries, including brain ischemia, traumatic brain injury, and aging-associated neurodegeneration, such as Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). However, effects of ethanol on ER stress in the CNS receive less attention. In this review, we discuss recent progress in the study of ER stress in ethanol-induced neurotoxicity. We also examine the potential mechanisms underlying ethanol-mediated ER stress and the interaction among ER stress, oxidative stress and autophagy in the context of ethanol neurotoxicity.


Overview of automated immunohistochemistry.
The increasing demand for immunohistochemistry for clinical diagnostics, in combination with an ongoing shortage of staff in the histology laboratory, has brought about a need for automation in immunohistochemistry. The current automated staining platforms vary significantly in their design and capabilities. To review how technology has been applied to automating the process of immunohistochemical staining. Literature review, vendor interviews, and personal practice experience. Each of the commercially available, automated immunohistochemistry platforms has strategic design differences that produce advantages and disadvantages. Understanding those differences can help match the demands of testing volumes, turnaround time, standardization, and labor savings to the appropriate automated instrumentation.


[Family function among the bereaved in hard-hit areas 1 year after Wenchuan earthquake].
To investigate the family function among the bereaved in hard-hit areas 1 year after Wenchuan earthquake and to provide basic information for family reconstruction. A cross-sectional study was used to survey 264 bereaved who were selected according to the criteria in hard-hit areas after Wenchuan earthquake. The scores of family care function of the bereaved in hard-hit areas after Wenchuan earthquake were 6.52±2.65. Fifty percent of the participants' family kept in good state. The scores of the bereaved family cohesion ranged from 28 to 83 (64.22±9.18), and the scores of family adaptability ranged from 21 to 62 (41.84±6.62). There was no significant difference in the score of family cohesion between the bereaved family and the non-bereaved family (P>0.05). But the score of the family adaptability of the bereaved family was significantly lower than that of the non-bereaved family (P<0.05). The bereaved family types were as follows: 22.0% balanced type, 53.8% middle type and 24.2% extreme type. In the 16 family types, the "intimate-rigid" (24.6%), "intimate-regular" (19.7%) and "disengaged-rigid" (19.3%) type ranked the top three. The family care function of the bereaved in hard-hit areas after Wenchuan earthquake is damaged to different degrees. The main type of family is the middle type. The loss of relatives reduces the participant family adaptability. In the late intervention, we should help the bereaved improve and enhance family function, and promote family reconstruction of the bereaved.


ESHAP versus rituximab-ESHAP in frail patients with refractory diffuse large B-cell lymphoma.
Treatment for refractory lymphoma in frail patients (older, poor performance status, or concomitant diseases) has not been defined. A total of 100 frail patients naive to rituximab therapy were allocated to be treated with ESHAP (etoposide, methylprednisolone, cytosine arabinoside, and platinum; 53 patients) or RESHAP (rituximab plus ESHAP; 47 patients). Granulocyte colony-stimulating factor was used to ameliorate the presence of severe granulocytopenia. Overall response rate (ORR) and complete response (CR) were similar among ESHAP and R-ESHAP (ORR, 33 patients [62%] and 28 patients [60%], respectively; CR, 20 patients [37%] and 18 patients [36%], respectively). Actuarial curves at 5 years showed that progression-free survival (PFS) and overall survival (OS) were similar: 51% and 31% in the ESHAP arm and 50% and 26%, respectively, in R-ESHAP. Toxicity was severe in both groups; grade 4 granulocytopenia was observed in 30% and 32% of ESHAP and R-ESHAP arms, respectively. Viral infections were more frequent in R-ESHAP (52 cases) than in ESHAP (3 cases). Frail patients, who generally have not been accepted in controlled clinical trials, can be treated with aggressive chemotherapy because tolerance is well and improvement in outcome is feasible. Although ESHAP retains the clinical efficacy previously reported in nonfrail patients, the addition of rituximab did not improve response rate, PFS, or OS.


[Clinical and Prognostic Value of Serum Neutrophil Gelatinase-Associated Lipocalin in Patients With ST-Segment Elevation Myocardial Infarction].
to study clinical and prognostic significance of serum neutrophil gelatinase-associated lipocalin (s-NGAL) in patients with ST-segment elevation myocardial infarction (STEMI). Patients with STEMI (n=85) of less than 24 hours duration admitted to the Kemerovo Cardiology Dispensary were included in the study. s-NGAL levels (ng/ml) were measured on day 1 and 12 of hospital stay by ELISA using commercial kit. Reinfarction rate and mortality were assessed over 3-year follow-up. Median s-NGAL levels on day1 and 12 were 1.33 (0.36-1.90) and 1.63 (1.25-2.61) ng/ml, that corresponded to a 3.32- and 4.07-fold increase, respectively, compared to reference values. Between days 1 and 12 s-NGAL levels increased by 22.55 % (p=0.0009). Higher values of serum NGAL on day 12 of MI were associated with presence of renal structural lesions, three-vessel coronary artery disease and anterior MI. Patients who underwent percutaneous coronary intervention (PCI) demonstrated only a negligible increase of s-NGAL level by day 12 while in those not subjected to PCI 3-fold increase was observed. Patients with s-NGAL levels >2.6 ng/ml compared with other patients had higher mortality (9.52 vs 31.83%; odds ratio 4.42 [1.30-15.16], p=0.012). High values of serum NGAL in STEMI patients were associated with severe clinical status. s-NGAL level above 2.6 ng/ml on day 12 of hospital stay was associated with 4- fold increase of all-cause mortality during 3-year follow-up.


Interpersonal psychotherapy for the prevention of binge-eating disorder and adult obesity in an African American adolescent military dependent boy.
Military adolescent boys report similar levels of disordered-eating as their female counterparts. Yet, interventions for the prevention of full-threshold eating disorders in adolescent boys are lacking. Interpersonal psychotherapy (IPT), an evidenced-based therapy adapted for the prevention of BED and adult obesity, has been studied in adolescent girls, but it is unclear whether IPT might resonate with adolescent boys. The current case study elucidates the use of a 12-week IPT group intervention for the prevention of BED and adult obesity in adulthood for an African American adolescent military dependent boy with reported loss-of-control (LOC)-eating, obesity, and elevated mood symptoms. LOC-eating and body mass index metrics decreased immediately post-intervention and further decreased by one-year follow-up. Social functioning scores improved and anxiety and depression scores decreased from baseline to one-year follow-up. In contrast to previous observations among girls, these improvements were evidenced without the teen's explicit acknowledgement of the link between mood and eating behaviors. Although the mechanism of change may manifest differently than for girls, adapted IPT may be an effective intervention strategy for adolescent boys with LOC-eating and obesity who endorse elevated mood symptoms.


A Modified OSCE Assessing the Assimilation and Application of Ethical Principles Relevant to Obstetric and Gynaecological Practice.
To develop and evaluate a modified OSCE assessing the assimilation and application of a range of ethical principles relevant to Obstetric and Gynecological practice. Candidates for an SpR training rotation Methods. Twenty six candidates working in Obstetrics and Gynecology were presented with four questions covering a range of relevant ethical scenarios. Their responses were assessed using a marking schedule. The marking schedule was evaluated against a checklist developed for assessing postgraduate medical examinations. Inter-rater reliability was assessed by calculating Kappa values for each question. The items in the marking schedule were also assessed to determine the level of agreement between the two examiners. To assess the contribution of each question to the total score, the question to total score correlations were calculated. The discriminatory capacity of each question was also assessed. The development of the examination met almost all of the criteria in the checklist for developing a postgraduate examination. Inter-rater reliability was reasonable (4 weighted Kappas ranged from 0.53 - 0.75). There was a high level of agreement between examiners as to whether a candidate had answered an item on the marking schedule correctly. The degree of discrimination of items in the marking schedule was consistent with clinical opinion on the importance of questions. This modified OSCE examination demonstrates the feasibility of testing ethical principles relevant to practice in Obstetrics and Gynecology in candidates for postgraduate posts. It meets most of the criteria laid down in a checklist developed to assess postgraduate medical examinations.


Chronicity of Anterior Cruciate Ligament Deficiency, Part 1: Effects on the Tibiofemoral Relationship Before and Immediately After Anatomic ACL Reconstruction With Autologous Hamstring Grafts.
It remains unclear whether the tibiofemoral relationship in the sagittal plane is restored after anatomic anterior cruciate ligament (ACL) reconstruction, particularly in cases of chronic ACL deficiency (ACLD). Patients with long-term ACLD will exhibit an anteriorly subluxed tibia both preoperatively and immediately postoperatively, even after anatomic reconstruction. Cohort study; Level of evidence, 2. In total, 358 patients who had undergone anatomic ACL reconstruction with autologous semitendinosus grafts were divided into 5 groups based on chronicity of ACLD: (1) 0 to 6 months, (2) 6 months to 1 year, (3) 1 to 2 years, (4) 2 to 5 years, and (5) longer than 5 years. Preoperatively and immediately postoperatively, all patients underwent lateral radiography in extension to evaluate the tibiofemoral relationship, specifically with regard to anterior tibial subluxation (ATS), space for the ACL (sACL), and extension angle. Demographic and radiographic factors were compared among the 5 groups. Preoperative ATS values in groups 4 (mean ± SD, 2.9 ± 2.1 mm) and 5 (2.6 ± 1.9 mm) were significantly greater than in group 1 (1.6 ± 1.9 mm). Postoperatively, the tibia was posteriorly overconstrained in all groups, and there was no difference in immediately postoperative ATS among the 5 groups. Further evaluation of the tibiofemoral relationship in the sagittal plane revealed that the mean preoperative side-to-side difference in sACL (sACL-SSD) was greater in groups 4 (2.5 ± 1.6 mm) and 5 (2.2 ± 1.7 mm) than in group 1 (1.2 ± 1.5 mm). Immediately after ACL reconstruction, however, there were no group-dependent differences in sACL-SSD. No significant group-dependent differences were found for extension deficit. Chronicity of ACLD had an effect on the preoperative tibiofemoral relationship in the sagittal plane, including ATS and sACL-SSD, especially in patients with ACLD longer than 2 years. However, preoperative extension deficit was not influenced by chronicity. Immediately postoperatively, chronicity did not affect the ability of anatomic ACL reconstruction to reduce subluxation.


Systolic blood pressure response to exercise as a predictor of mortality in patients with chronic heart failure.
It is well known that peak oxygen consumption and heart rate (HR) recovery after exercise obtained from the cardiopulmonary exercise test are prognostic parameters in patients with chronic heart failure (CHF). However, it is unclear whether exercise-induced parameters obtained from the routine exercise stress test predict mortality in patients with CHF. We studied 136 patients (93 males/43 females) with CHF. All patients underwent symptom-limited exercise stress testing. Exercise parameters included exercise duration, exercise-induced HR and systolic blood pressure (SBP), and metabolic equivalents (METs). During the follow-up period (mean 6.2 years), 34 patients died. Survival rates at the 3rd and 5th years were 90% and 83%, respectively. Body mass index was significantly smaller in the nonsurvival group than in the survival group (P < 0.01). The incidence of patients with New York Heart Association III class was higher in the nonsurvival group than in the survival group (P < 0.05). In univariate analysis, predictors of mortality included peak HR and SBP, increases in HR and SBP during exercise, HR and SBP at the 1st minute after exercise, HR at the 3rd minute after exercise, and METs. The use of beta-adrenergic blocking agents was not associated with prognosis. In Cox hazard model analysis, the increase in SBP (P < 0.002), HR at the 3rd minute after exercise (P < 0.05), and METs (P < 0.05) were independent predictors of mortality. SBP response to exercise, HR recovery after exercise, and METs obtained from the routine exercise test predicted mortality in patients with CHF irrespective of the use of beta-adrenergic blocking agents.


Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the german high-grade non-Hodgkin lymphoma study group.
To study pharmacokinetics, toxicity, and efficacy of prolonged rituximab exposure in elderly patients with diffuse large B-cell lymphoma (DLBCL). In the SMARTE-R-CHOP-14 trial, rituximab 375 mg/m(2) was administered, together with six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone on a 14-day schedule (6×R-CHOP-14), on days -4, 0, 10, 29, 57, 99, 155, and 239. Pharmacokinetics and outcome were to be compared with those of patients who had received 6×R-CHOP-14 in combination with eight 2-week applications of rituximab in the RICOVER-60 (Rituximab With CHOP Over Age 60 Years) trial. The complete response (CR)/unconfirmed CR rate was 85% in 189 evaluable patients, 90% for 90 good-prognosis patients (International Prognostic Index [IPI], 1 or 2), and 81% for 99 poor-prognosis patients (IPI, 3 to 5); 3-year event-free survival (EFS) was 71%, 75%, and 67%, respectively; and 3-year overall survival (OS) was 84%, 88%, and 80%, respectively, with no differences between men and women. The preplanned historical comparison with 306 RICOVER-60 patients (good prognosis, n = 183; poor prognosis, n = 123) revealed no outcome differences for all and good-prognosis patients; however, the longer exposure time in SMARTE-R-CHOP-14 compared with RICOVER-60 was associated with better 3-year EFS (67% v 54%) and OS (80% v 67%) in poor-prognosis patients. Extended rituximab exposure compared with eight 2-week applications in combination with 6×R-CHOP-14 significantly improved outcome of elderly poor-prognosis patients without increasing toxicity. To our knowledge, results obtained with the SMARTE-R-CHOP-14 rituximab schedule are the best reported for elderly patients with DLBCL to date. In the subgroup of poor-prognosis patients treated with extended rituximab exposure, the outcome seemed superior to that of a similar historical cohort of patients treated with 6×R-CHOP-14 plus 2-week rituximab, with similar toxicity. A randomized comparison of the two schedules is warranted.


Correlates of bone and blood lead levels among middle-aged and elderly women.
In 1993-1995, the authors evaluated risk factors for elevated blood and bone lead levels in 264 Boston, Massachusetts, area women previously selected for a case-control study of lead and hypertension. Bone lead was measured at the tibia and patella with K x-ray fluorescence. Blood lead was analyzed by graphite furnace atomic absorption. Participants were aged 46-74 years and had mean lead levels of 3 (standard deviation, 2) micro g/dl (blood), 13 (standard deviation, 9) micro g/g (tibia), and 17 (standard deviation, 11) micro g/g (patella). In multivariate linear regression models, use of postmenopausal estrogen (inverse) and alcohol intake (positive) were significantly associated with blood lead levels. Both bone lead measures were significantly and positively associated with blood lead but only among postmenopausal women not using estrogen; for example, an increase from the first to the fifth quintile of tibia lead level (19 micro g/g) was associated with a 1.7- micro g/dl increase in blood lead (p = 0.0001) in this group. Older age and lower parity were associated with higher tibia lead; only age was associated with patella lead. The observed interaction of bone lead with estrogen status in determining blood lead supports the hypothesis that increased bone resorption, as occurs postmenopausally because of decreased estrogen production, results in heightened release of bone lead stores into blood.


Neonatal Glycogen Storage Disease Type IA: A Rare Presentation.
Glucose homeostasis is essential for energy production and the central nervous system function, depending on glycogen metabolism. Glycogen storage diseases (GSD) are caused by enzymatic defects of the glycogen degradation and mainly involve the liver since the inhibition of hepatic glycogen breakdown results in its excessive storage and hepatomegaly. Other findings are hypoglycemia and hyperlactatemia and consequent neurological symptoms. GSD Type Ia is a severe disease with clinical manifestations usually occurring in the first months. Morbidity and mortality are high, when not treated. The patient was a male newborn, with nonconsanguineous couple, born by eutocic delivery and weight 3760 g. On Day 2, weight loss >10% and jaundice were noticed, and physical examination was as normal. The investigation showed low glucose that only respond to iv glucose, metabolic acidosis, hyperlactatemia and elevated liver enzymes. Considering his inherited metabolic disease, he was transferred to the Reference Center. Complementary tests showed hypertriglyceridemia and absence of ketone bodies. Abdominal US revealed a liver in the upper limit of normal. Most likely clinical diagnosis was GSD type Ia, confirmed by genetic test. He needed iv glucose, but then stabilized with formula without galactose, supplemented with dextrin every 2 hours. He is now 7 months old, has flash glucose self-monitoring system, maintaining frequent feedings, with sporadic hypoglycemia with normal physical development and no hepatomegaly. Hypoglycemia and early weight loss in newborns are red flags for metabolic diseases or other conditions. When accompanied by other metabolic findings, such as hyperlactatemia and metabolic acidosis, associated with short fasting periods, glycogen metabolism disorders must be considered. Patients with GSD Type Ia generally appear normal at birth and an early presentation is not frequent within the first hours after birth. Moreover, avoiding fasting and hypoglycemia are of vital importance for better cognitive outcome, global prognosis, and prevention of other metabolic abnormalities.


Epidemiology and laboratory diagnoses of rubella in Hokkaido district during the Nationwide Outbreak in Japan, 2011-2013.
We report the epidemiology and laboratory diagnostic results of rubella cases from 2011 to 2013 in Hokkaido district, Japan. A total of 150 cases were officially reported as rubella; 102 (68%) involved males and 48 (32%) involved females. The highest proportion of cases were notified in 40-49-year-old age group among males and the 20-29-years-old age group among females. Forty-six cases (25 males and 21 females) had not been vaccinated, and 17 had been vaccinated, whereas 87 had the unknown vaccination status. Eighty-three cases (55.3%) showed the 3 typical principal rubella symptoms (fever, rash, and lymphadenopathy). Seven, 11, 92, and 40 cases were identified in the northern, eastern, central, and southern areas of Hokkaido district, respectively. In the central and southern areas of Hokkaido district, endemic rubella transmissions were indicated by both the epidemiological survey and molecular analyses. However, these outbreaks terminated spontaneously and did not expand to other areas of Hokkaido district. Fortunately, no congenital rubella syndrome (CRS) cases were reported during this observation period. However, to control virus transmission, prevent CRS, and maintain the routine vaccination program, the immediate introduction of an immunization strategy is required for susceptible individuals, particularly young adults.


Acute fulminant necrotizing colitis caused by amebiasis: report of a case.
Fulminating colitis rarely develops as a complication of amebiasis; however, it is difficult to diagnose and treat, and associated with a very high mortality rate. We report herein the case of a 62-year-old man with superacute fulminant necrotizing amebic colitis who, despite treatment with aggressive surgery and antiamebic agents, died of multiple organ failure following sepsis on the 25th day after onset. The patient had no immmunosuppressive disorders and claimed that he had never had homosexual intercourse, or traveled to the tropics in recent years. Since the incidence of amebiasis is increasing in developed countries, including Japan, more attention should be focused on the fulminating nature of this disease.


The high toxicity of DSB-clusters modelling high-LET-DNA damage derives from inhibition of c-NHEJ and promotion of alt-EJ and SSA despite increases in HR.
Heavy-ion radiotherapy utilizing high linear energy transfer (high-LET) ionizing radiation (IR) is a promising cancer treatment modality owing to advantageous physical properties of energy deposition and associated toxicity over X-rays. Therapies utilizing high-LET radiation will benefit from a better understanding of the molecular mechanisms underpinning their increased biological efficacy. Towards this goal, we investigate here the biological consequences of well-defined clusters of DNA double-strand breaks (DSBs), a form of DNA damage, which on theoretical counts, has often been considered central to the enhanced toxicity of high-LET IR. We test clonal cell lines harboring in their genomes constructs with appropriately engineered I-SceI recognition sites that convert upon I-SceI expression to individual DSBs, or DSB-clusters comprising known numbers of DSBs with defined DNA-ends. We find that, similarly to high-LET IR, DSB-clusters of increasing complexity, i.e. increasing numbers of DSBs, with compatible or incompatible ends, compromise classical non-homologous end-joining, favor DNA end-resection and promote resection-dependent DSB-processing. Analysis of RAD51 foci shows increased engagement of error-free homologous recombination on DSB-clusters. Multicolor fluorescence in situ hybridization analysis shows that complex DSB-clusters markedly increase the incidence of structural chromosomal abnormalities (SCAs). Since RAD51-knockdown further increases SCAs-incidence, we conclude that homologous recombination suppresses SCAs-formation. Strikingly, CtIP-depletion inhibits SCAs-formation, suggesting that it relies on alternative end-joining or single-strand annealing. Indeed, ablation of RAD52 causes a marked reduction in SCAs, as does also inhibition of PARP1. We conclude that increased DSB-cluster formation that accompanies LET-increases, enhances IR-effectiveness by promoting DNA end-resection, which suppresses c-NHEJ and enhances utilization of alt-EJ or SSA. Although increased resection also favors HR, on balance, error-prone processing dominates, causing the generally observed increased toxicity of high-LET radiation. These findings offer new mechanistic insights into high-LET IR-toxicity and have translational potential in the clinical setting that may be harnessed by combining high-LET IR with inhibitors of PARP1 or RAD52.


Masking-level difference for spondaic words in 2000-msec bursts of broadband noise.
One protocol developed for the Tonal and Speech Materials for Auditory Perceptual Assessment audio compact disc was the masking-level difference (MLD) for spondaic words in which the words and broadband noise were mixed and recorded at 16 selected signal-to-noise ratios. Four words were recorded at each level. Because it was impossible to monitor the word presentations at negative signal-to-noise ratios, a different paradigm was devised in which the spondaic words were embedded in 2000-msec bursts of noise. Before the materials were finalized for the compact disc, two experiments studied the perceptual characteristics of the paradigm. Experiment I was performed to determine the characteristics of the MLD for spondaic words in 2000-msec bursts of noise at 70 dB SPL. An unexpected finding was that the mean SoNo thresholds were at signal-to-noise ratios 3-4 dB lower than previously reported spondaic word thresholds in continuous broadband noise. Experiment II examined this discrepancy with the spondaic words embedded in continuous noise and in the 2000-msec noise bursts. The results confirmed the 3-4 dB difference between thresholds for the two masker conditions. Based on the pilot data, the spondaic words embedded in 2000-msec bursts of broadband noise at signal-to-noise ratios of 0 dB to -30 dB were recorded on the compact disc in the S pi No paradigm. In the compact disc trials, which involved 120 subjects with normal hearing, the MLDs for the spondaic words recorded on the compact disc were measured on 60 subjects at each of two noise levels.(ABSTRACT TRUNCATED AT 250 WORDS)


Sublingual floor of Rahmani sheep (Ovis aries): A scanning electron microscopy and histomorphology analysis.
The current study investigated the sublingual floor of Rahmani sheep (Ovis aries). Samples from nine healthy adult sheep have been analysed using morphometrical, scanning electron microscopic (SEM), and histological examination. The sublingual floor of the sheep was formed of a rostral prefrenular part (spatula-shaped) and two lateral sublingual recesses. Right and left sublingual caruncles were asymmetrical in length and each one had a serrated border, divided into three papillae. At higher magnifications, the three papillae of the sublingual caruncle's edge were variable in shape, with other two papillae were demonstrated underneath the caruncle. Each sublingual recess had a sublingual fold (plica sublingualis) extended from the level of frenulum linguae till the glossopalatine arch, bordered with caudolaterally directed papillae till the level of first lower molar cheek teeth. The sublingual salivary glands were mixed (seromucoid) type. The glandular lobule consisted of mucous acini and sporadic serous acini, as well as the presence of some mucous acini capped by acidophilic cells, serous demilunes. The mucous acinus was formed of pyramidal mucous cells with pale stained cytoplasm and basally located nuclei. Two ducts; major sublingual and submandibular ducts were observed within the submucosa of the sublingual caruncle. The sublingual ductal pseudostratified columnar epithelium was interspersed by more goblet cells than that of the submandibular duct. Collagen fibres around the glandular lobules, intralobular and interlobular excretory ducts as well as the connective core of the papillae were noticed. By SEM, two epithelium-lined pits on the surface of the sublingual floor mucosa caudal to the central incisive teeth were termed orobasal organ. As the first study to give a comprehensive analysis of the sheeps' sublingual floor, this one serves as a baseline for future clinical studies.


Reporting Race and Ethnicity in Genetics Research: Do Journal Recommendations or Resources Matter?
Appeals to scrutinize the use of race and ethnicity as variables in genetics research notwithstanding, these variables continue to be inadequately explained and inconsistently used in research publications. In previous research, we found that published genetic research fails to follow suggestions offered for addressing this problem, such as explaining the basis on which these labels are assigned to populations. This study, an analysis of genetic research articles using race or ethnicity terms, explores possible features of journals that are associated with improved reporting of race and ethnicity in genetic research. A journal's expressed commitment to improving how race and ethnicity are used in genetic research, demonstrated by an editorial or in its instructions to authors, was the strongest predictor of following recommendations about reporting race and ethnicity. Journal impact factor had only a limited positive effect on attention to these issues, suggesting that editorial resources associated with higher impact factor journals are not sufficient to improve practices. Our findings reiterate that race and ethnicity variables are used inconsistently in genetic research, but also shed light on how journals might improve practices by highlighting the need for scientists to carefully scrutinize the use of these variables in their work.


The Differential Impact of User-Fee Exemption Compared to Conditional Cash Transfers on Safe Deliveries in Nepal.
To assess the differential impact of a copayment exemption compared to a cash incentive on increasing skilled birth attendance (i.e., birth attended by a skilled health worker) in Nepal. This study used data on 8,785 children born between July 2005 and December 2008, obtained from the nationally representative Demographic and Health Surveys, 2006 and 2011. Twenty-five districts received both the policy interventions, and the remaining 50 control districts received only the cash incentive. We employed a difference-in-differences model to compare children born in districts with both interventions to those in districts with conditional cash transfers only. Average marginal effects of the difference-in-difference coefficient on skilled birth attendance measures are estimated. Skilled birth attendance in districts with both interventions was no higher on average than in districts with only the cash incentive. In areas with adequate road networks, however, significantly higher skilled birth attendance was observed in districts with both interventions compared to those with only the cash incentive. The added incentive of the user-fee exemption did not significantly increase skilled birth attendance relative to the presence of the cash incentive. User-fee exemptions may not be effective in areas with inadequate road infrastructure.


Nicotinic acid increases adiponectin secretion from differentiated bovine preadipocytes through G-protein coupled receptor signaling.
The transition period in dairy cows (3 weeks prepartum until 3 weeks postpartum) is associated with substantial mobilization of energy stores, which is often associated with metabolic diseases. Nicotinic acid (NA) is an antilipolytic and lipid-lowering compound used to treat dyslipidaemia in humans, and it also reduces non-esterified fatty acids in cattle. In mice the G-protein coupled receptor 109A (GPR109A) ligand NA positively affects the secretion of adiponectin, an important modulator of glucose and fat metabolism. In cattle, the corresponding data linking NA to adiponectin are missing. Our objective was to examine the effects of NA on adiponectin and AMPK protein abundance and the expression of mRNAs of related genes such as chemerin, an adipokine that enhances adiponectin secretion in vitro. Differentiated bovine adipocytes were incubated with pertussis toxin (PTX) to verify the involvement of GPR signaling, and treated with 10 or 15 µM NA for 12 or 24 h. NA increased adiponectin concentrations (p ≤ 0.001) and the mRNA abundances of GPR109A (p ≤ 0.05) and chemerin (p ≤ 0.01). Pre-incubation with PTX reduced the adiponectin response to NA (p ≤ 0.001). The NA-stimulated secretion of adiponectin and the mRNA expression of chemerin in the bovine adipocytes were suggestive of GPR signaling-dependent improved insulin sensitivity and/or adipocyte metabolism in dairy cows.


Tests of shielding effectiveness of Kevlar and Nextel onboard the International Space Station and the Foton-M3 capsule.
Radiation assessment and protection in space is the first step in planning future missions to the Moon and Mars, where mission and number of space travelers will increase and the protection of the geomagnetic shielding against the cosmic radiation will be absent. In this framework, the shielding effectiveness of two flexible materials, Kevlar and Nextel, were tested, which are largely used in the construction of spacecrafts. Accelerator-based tests clearly demonstrated that Kevlar is an excellent shield for heavy ions, close to polyethylene, whereas Nextel shows poor shielding characteristics. Measurements on flight performed onboard of the International Space Station and of the Foton-M3 capsule have been carried out with special attention to the neutron component; shielded and unshielded detectors (thermoluminescence dosemeters, bubble detectors) were exposed to a real radiation environment to test the shielding properties of the materials under study. The results indicate no significant effects of shielding, suggesting that thin shields in low-Earth Orbit have little effect on absorbed dose.


Comparative Sensitivity Analysis of Muscle Activation Dynamics.
We mathematically compared two models of mammalian striated muscle activation dynamics proposed by Hatze and Zajac. Both models are representative for a broad variety of biomechanical models formulated as ordinary differential equations (ODEs). These models incorporate parameters that directly represent known physiological properties. Other parameters have been introduced to reproduce empirical observations. We used sensitivity analysis to investigate the influence of model parameters on the ODE solutions. In addition, we expanded an existing approach to treating initial conditions as parameters and to calculating second-order sensitivities. Furthermore, we used a global sensitivity analysis approach to include finite ranges of parameter values. Hence, a theoretician striving for model reduction could use the method for identifying particularly low sensitivities to detect superfluous parameters. An experimenter could use it for identifying particularly high sensitivities to improve parameter estimation. Hatze's nonlinear model incorporates some parameters to which activation dynamics is clearly more sensitive than to any parameter in Zajac's linear model. Other than Zajac's model, Hatze's model can, however, reproduce measured shifts in optimal muscle length with varied muscle activity. Accordingly we extracted a specific parameter set for Hatze's model that combines best with a particular muscle force-length relation.


Relationship between bacteriology of the adenoid core and middle meatus in children with sinusitis.
To assess the correlation between bacterial pathogens in the adenoid core and the middle meatus, in children with hypertrophied adenoids and chronic or recurrent sinusitis. The study was conducted at Alexandria University Hospitals. We included 103 children aged four to 12 years who were scheduled for adenoidectomy and who had clinical and/or radiological evidence of chronic or recurrent sinusitis. Adenoid core specimens and middle meatal swabs were obtained from every patient and were sent for bacteriological evaluation using standard qualitative and quantitative microbiological techniques. The results were statistically analysed. The bacterial species isolated most frequently from the adenoid core were coagulase-negative staphylococci (40.8 per cent), Staphylococcus aureus (22.3 per cent), Streptococcus pneumoniae (18.4 per cent), Haemophilus influenzae (16.5 per cent) and group A streptococci (15.5 per cent). The bacterial species isolated most frequently from the middle meatus were coagulase-negative staphylococci (41.7 per cent), S aureus (32 per cent), S pneumoniae (28.1 per cent), H influenzae (21.6 per cent) and group A streptococci (19.4 per cent). The adenoid core and middle meatal cultures were both positive for at least one bacterial species in 63 cases, and were both negative in 25 cases. In six cases, a positive adenoid core culture was associated with a negative middle meatal culture. In five cases, a negative adenoid core culture was associated with a positive middle meatal culture (for one or more pathogenic species). Thus, adenoid core culture had a positive predictive value of 91.5 in forecasting the middle meatal culture result, and a negative predictive value of 84.3. Apart from its effect on nasal airway patency, adenoidal tissue may function as a bacterial reservoir initiating and maintaining sinus infection in children. These study findings support a potential role for adenoidectomy in the treatment of chronic or recurrent paediatric sinusitis.


H2O2 recycling during oxidation of the arylglycerol beta-aryl ether lignin structure by lignin peroxidase and glyoxal oxidase.
Oxidative C alpha-C beta cleavage of the arylglycerol beta-aryl ether lignin model 1-(3,4-dimethoxy-phenyl)-2-phenoxypropane-1,3-diol (I) by Phanerochaete chrysosporium lignin peroxidase in the presence of limiting H2O2 was enhanced 4-5-fold by glyoxal oxidase from the same fungus. Further investigation showed that each C alpha-C beta cleavage reaction released 0.8-0.9 equiv of glycolaldehyde, a glyoxal oxidase substrate. The identification of glycolaldehyde was based on 13C NMR spectrometry of reaction product obtained from beta-, gamma-, and beta,gamma-13C-substituted I, and quantitation was based on an enzymatic NADH-linked assay. The oxidation of glycolaldehyde by glyoxal oxidase yielded 0.9 oxalate and 2.8 H2O2 per reaction, as shown by quantitation of oxalate as 2,3-dihydroxyquinoxaline after derivatization with 1,2-diaminobenzene and by quantitation of H2O2 in coupled spectrophotometric assays with veratryl alcohol and lignin peroxidase. These results suggest that the C alpha-C beta cleavage of I by lignin peroxidase in the presence of glyoxal oxidase should regenerate as many as 3 H2O2. Calculations based on the observed enhancement of LiP-catalyzed C alpha-C beta cleavage by glyoxal oxidase showed that approximately 2 H2O2 were actually regenerated per cleavage of I when both enzymes were present. The cleavage of arylglycerol beta-aryl ether structures by ligninolytic enzymes thus recycles H2O2 to support subsequent cleavage reactions.


[Novelties in the diagnostics and therapy of hairy cell leukemia].
Differential diagnosis of hairy cell leukemia (HCL) and related disorders (hairy cell leukemia variant and splenic marginal zone lymphoma) is of utmost importance since the treatment and prognosis of these lymphomas differ. Since 2011 diagnosis of hairy cell leukemia has been easier because of discovery of the disease defining somatic mutation BRAF V600E mutation, which has been also known as driver mutation in malignant melanoma. The presence of this mutation enabled targeted molecular therapy in HCL as well. As first line therapy purine nucleoside analogues are the gold standard, but refractory/relapsed patient are candidates for targeted BRAF-inhibitor therapy. This manuscript serves as guidance in making diagnosis and standard treatment of HCL, and summarizes newest data about molecular therapy, including our single center experience collected from 75 patients.


Amnesia and crime: a neuropsychiatric response.
Bourget and Whitehurst's "Amnesia and Crime," published in a prior issue of the Journal, addresses a conceptually complex and clinically challenging subject. Their treatment emphasizes psychiatric conditions in which memory disturbances may arise that are relevant to criminal proceedings. However, their consideration of the neurobiology of memory, memory disturbances, and the neurobiological bases of interactions between psychiatric symptoms and memory merit further elaboration. The relevance of memory impairment to criminal matters requires forensic psychiatric experts to possess a basic understanding of the phenomenology and neurobiology of memory. The present authors describe briefly the phenomenology and neuroanatomy of memory, emphasizing first that memory is not a unitary cognitive domain, clinically or neurobiologically. The assertion that psychotic delusions produce memory impairment is challenged, and the description of "organic" amnesia, both semantically and in terms of its clinical features, is reframed. Resources on which to build a neuropsychiatric foundation for forensic psychiatric opinions on memory impairment surrounding criminal behavior are offered.


IMAGE REGISTRATION WITH OPTIMAL REGULARIZATION PARAMETER SELECTION BY LEARNED AUTO ENCODER FEATURES.
In this paper, we propose a method that optimizes a regularization parameter for the regularized Free Form Deformation (FFD) non-rigid image registration. The developed process utilizes autoencoder generated image representations to assess image data generalization quality by the regularization parameter. Both pixel intensity and learned features are used to improve the overall accuracy and regularity of the resulting inverse problem solution. We implement the new selection criterion with its use in the non-rigid image FFD registration based on multi-level Bspline with L2-regularization, and validate the method with synthetic and real histopathology image datasets. Both qualitative and quantitative results suggest the efficacy of our developed method for fine-tuning histopathology microscope images.


Selective decontamination of the digestive tract: risks outweigh benefits for intensive care unit patients.
Selective decontamination of the digestive tract (SDD) involves the administration of non-absorbable antibiotics (+/- a systemic antibiotic) to prevent colonization and infection in intensive care unit patients. The regimen is targeted at nosocomial gram-negative bacilli, some gram-positive bacteria and yeast. Although all studies of SDD have demonstrated reduced rates of bacterial colonization and most yielded lower respiratory tract infection, it is unclear if the major impact of SDD is on pneumonia or tracheobronchitis. SDD regimens utilizing a broad spectrum, systemic antibiotic appear to be more effective, suggesting that this constitutes early treatment rather than prophylaxis. To date, there is conflicting evidence that SDD significantly reduces length of stay, mortality, or hospital costs. Currently, there are concerns that SDD may result in increased colonization and infection with gram-positive organisms and multi-drug resistant pathogens, particularly in medical ICU patients or when used for extended periods of time.


Characterization and expression of steroidogenic acute regulatory protein and MLN64 cDNAs in trout.
Complementary DNA-encoding proteins with high homology to steroidogenic acute regulatory proteins (StAR) of mammals were cloned from rainbow trout head kidney and a mixture of several brook trout tissues. A cDNA encoding an MLN64 homolog was also cloned from brook trout. The C-terminal domains of rainbow trout StAR and brook trout StAR were very highly conserved compared with StAR of mammals. In rainbow trout, Northern and RT-PCR analyses showed abundant StAR transcripts in head kidney, ovary, and testis, and weaker signals were found in intestine, pyloric caeca, spleen, and kidney. Brief acute stress resulted in elevated plasma cortisol levels and a 2-fold increase in rainbow trout StAR transcripts in head kidneys sampled 3 h after exposure to the stressor. In brook trout, StAR transcripts were detected only in known steroidogenic tissues. Ovarian brook trout StAR mRNA was not seen until the onset of final maturation. Its abundance increased during germinal vesicle breakdown, peaked during and just following ovulation, and decreased by 2 wk post ovulation. Brook trout MLN64 transcripts were found in all tissues tested, and transcript abundance in ovarian samples did not vary during final oocyte maturation and ovulation. Both StAR structure and function appear to be highly conserved throughout the vertebrates.


Perceptions of and Practices for the Management of Constipation: Results of a Korean National Survey.
Although guidelines exist regarding the evaluation and management of patients with chronic constipation (CC), little is known about real-world clinical practice patterns. This study aimed to evaluate the various practices used to manage CC patients in various clinical settings in South Korea. A nationwide web-based survey was conducted, randomly selecting gastroenterologists and non-gastroenterologists. The 25-item questionnaire included physicians' perceptions and practices regarding the available options for diagnosing and managing CC patients in Korea. The study participants comprised 193 physicians (86 gastroenterologists, 44.6%) involved in the clinical management of CC patients. The mean clinical experience was 12 years. Only 21 of 193 respondents (10.9%) used the Rome criteria when diagnosing CC. The Bristol Stool Form Scale was used by 29% of the respondents (56/193), while the digital rectal examination was performed by 11.9% of the respondents (23/193). Laboratory testing and colonoscopies were performed more frequently by gastroenterologists than by non-gastroenterologists (both p=0.001). Physiologic testing was used more frequently by gastroenterologists (p=0.046), physicians at teaching hospitals, and physicians with clinical experience ≤10 years (both p<0.05). There were also significant differences in the preference for laxatives depending on the type of hospital. There were discrepancies in the diagnosis and management of CC patients depending on the clinical setting. The utilization rates of the Bristol Stool Form Scale and digital rectal examination by physicians are low in real-world clinical practice. These results imply the need for better and more practical training of physicians in the assessment and management of CC.


Hydrophobically modified carboxymethyl chitosan nanoparticles targeted delivery of paclitaxel.
Specific targeting of tumor cells to achieve higher drug levels in tumor tissue and to overcome the side effects is the major goal in cancer therapy. Nanoparticles encapsulating a hydrophobic core in their nanoreservoir structure were developed as a carrier for a water-insoluble drug, paclitaxel. In the present study, target-oriented nanoparticles based on biodegradable O-carboxymethyl chitosan modified with stearic acid. The surface of the nanoparticles was modified by covalent attachment of folic acid (FA) by simple carbodimide reaction to achieve tumor cell targeting property. Nanoparticles were prepared by the sonication method without involving any surfactants/emulsifiers. The nanoparticles were characterized by various state-of-the-art techniques, including laser light scattering for particles size distribution, field emission scanning electron microscopy and transmission electron microscope for surface morphology. The drug release property and the cytotoxicity of the drug loaded nanoparticles to both cancerous and noncancerous cells were evaluated in cell culture system. To our knowledge, this is the first study demonstrating a FA modified hydrophobically chitosan with paclitaxel-loaded nanoparticles targeting of folate receptor overexpressing cancer cells.


Recruitment and Regulation of the Non-ribosomal Peptide Synthetase Modifying Cytochrome P450 Involved in Nikkomycin Biosynthesis.
The β-hydroxylation of l-histidine is the first step in the biosynthesis of the imidazolone base of the antifungal drug nikkomycin. The cytochrome P450 (NikQ) hydroxylates the amino acid while it is appended via a phosphopantetheine linker to the non-ribosomal peptide synthetase (NRPS) NikP1. The latter enzyme is comprised of an MbtH and single adenylation and thiolation domains, a minimal composition that allows for detailed binding and kinetics studies using an intact and homogeneous NRPS substrate. Electron paramagnetic resonance studies confirm that a stable complex is formed with NikQ and NikP1 when the amino acid is tethered. Size exclusion chromatography is used to further refine the principal components that are required for this interaction. NikQ binds NikP1 in the fully charged state, but binding also occurs when NikP1 is lacking both the phosphopantetheine arm and appended amino acid. This demonstrates that the interaction is mainly guided by presentation of the thiolation domain interface, rather than the attached amino acid. Electrochemistry and transient kinetics have been used to probe the influence of l-His-NikP1 binding on catalysis by NikQ. Unlike many P450s, the binding of substrate fails to induce significant changes on the redox potential and autoxidation properties of NikQ and slows down the binding of dioxygen to the ferrous enzyme to initiate catalysis. Collectively, these studies demonstrate a complex interplay between the NRPS maturation process and the recruitment and regulation of an auxiliary tailoring enzyme required for natural product biosynthesis.


Liquid chromatographic determination of ornithine and lysine based on intramolecular excimer-forming fluorescence derivatization.
A highly sensitive and selective fluorometric determination method for ornithine and lysine has been developed. This method is based on an intramolecular excimer-forming fluorescence derivatization with a pyrene reagent, 4-(1-pyrene)butyric acid N-hydroxysuccinimide ester (PSE), followed by reversed-phase liquid chromatography (LC). The analytes, containing two amino moieties in a molecule, were converted to the corresponding dipyrene-labeled derivatives by reaction with PSE. The derivatives afforded intramolecular excimer fluorescence (450-550 nm) which can clearly be discriminated from the normal fluorescence (370-420 nm) emitted from PSE and monopyrene-labeled derivatives of monoamines. The structures of the derivatives and the emission of excimer fluorescence were confirmed by LC with mass spectrometry and with three-dimensional fluorescence detection system, respectively. The PSE derivatives of ornithine and lysine could be separated by reversed-phase LC on ODS column with isocratic elution. The detection limits (signal-to-noise ratio = 3) for ornithine and lysine were 3.5 and 3.7 fmol, respectively, for a 20-microl injection. Furthermore, this method had enough selectivity and sensitivity for the determination of ornithine and lysine in normal human urine.


INTRODUCTION OF UNIVERSAL HEALTH PROGRAM IN GEORGIA: PROBLEMS AND PERSPECTIVES.
Since 2013, Georgia enacted Universal Healthcare (UHC) program. Inclusion of uninsured population in the UHC program will have a positive impact on their financial accessibility to the health services. The study aims to analyze the referral rate of the beneficiaries to the health service providers before introduction and after application of the UHC program, particularly, how much it increased the recently uninsured population referral to primary health care units, and also to study the level of satisfaction with the UHC program. Research was conducted by qualitative and quantitative methods. The target groups' (program beneficiaries, physicians, personnel of the Social Service Agency) opinions were identified by means of face-to-face interviews. Enactment of the UHC programs significantly raised the population refferal to the family physicians, and the specialists. Insignificantly, but also increased the frequency of laboratory and diagnostic services. Despite the serious positive changes caused by UHC program implementation there still remain the problems in the primary healthcare system. Also, it is desirable to raise the financial availability of those medical services, which may cause catastrophic costs. In this respect, such medical services must be involved in the universal healthcare program and been expanded their scale. For the purpose of effective usage of the limited funds allocated for health care services provision, the private health insurance companies should be involved in UHC programs. This, together with the reduction of health care costs will increase a competition in the medical market, and enhance the quality of health service.


Symptom perception by nonpsychiatric physicians in evaluating for depression.
A questionnaire was constructed and used to assess the perception of symptoms of a depressive disorder by nonpsychiatric physicians in patient evaluations. Results showed that respondents consistently perceived depression as resulting from psychological rather than biological factors. It is suggested that such perception on the part of physicians may hinder consolidation of a patient's symptom complex with the degree of certainty necessary for a diagnostic consideration of depressive disorder.


Glycoprotein hormone alpha subunit secretion by pituitary adenomas: influence of external irradiation.
In ninety-nine patients with pituitary adenomas, forty-six with acromegaly, the serum level of the glycoprotein hormone alpha subunit was elevated in eighteen cases. Thirteen of these were acromegalic and one had an FSH-producing tumour. Alpha levels varied little during the day, from one day to the next and over a 6 month period. In twenty-five patients with a variety of other hypothalamic-pituitary disorders examined, one patient with a craniopharyngioma had a mildly elevated alpha level. External pituitary irradiation was followed by an acute and often transient fall in alpha level in several of these patients. Of the fifty-four patients with pituitary adenomas who had received external irradiation before testing, only five had elevated alpha subunit levels compared with thirteen patients of the forty-five who had not been irradiated. This difference in incidence of elevated alpha level was statistically significant (P less than 0.025). We conclude that external irradiation may reduce alpha subunit level chronically in many patients with pituitary adenoma.


Cysteine desulfurase Nfs1 and Pim1 protease control levels of Isu, the Fe-S cluster biogenesis scaffold.
Fe-S clusters are critical prosthetic groups for proteins involved in various critical biological processes. Before being transferred to recipient apo-proteins, Fe-S clusters are assembled on the highly conserved scaffold protein Isu, the abundance of which is regulated posttranslationally on disruption of the cluster biogenesis system. Here we report that Isu is degraded by the Lon-type AAA+ ATPase protease of the mitochondrial matrix, Pim1. Nfs1, the cysteine desulfurase responsible for providing sulfur for cluster formation, is required for the increased Isu stability occurring after disruption of cluster formation on or transfer from Isu. Physical interaction between the Isu and Nfs1 proteins, not the enzymatic activity of Nfs1, is the important factor in increased stability. Analysis of several conditions revealed that high Isu levels can be advantageous or disadvantageous, depending on the physiological condition. During the stationary phase, elevated Isu levels were advantageous, resulting in prolonged chronological lifespan. On the other hand, under iron-limiting conditions, high Isu levels were deleterious. Compared with cells expressing normal levels of Isu, such cells grew poorly and exhibited reduced activity of the heme-containing enzyme ferric reductase. Our results suggest that modulation of the degradation of Isu by the Pim1 protease is a regulatory mechanism serving to rapidly help balance the cell's need for critical iron-requiring processes under changing environmental conditions.


Efficient Carrier-to-Exciton Conversion in Field Emission Tunnel Diodes Based on MIS-Type van der Waals Heterostack.
We report on efficient carrier-to-exciton conversion and planar electroluminescence from tunnel diodes based on a metal-insulator-semiconductor (MIS) van der Waals heterostack consisting of few-layer graphene (FLG), hexagonal boron nitride (hBN), and monolayer tungsten disulfide (WS2). These devices exhibit excitonic electroluminescence with extremely low threshold current density of a few pA·μm-2, which is several orders of magnitude lower compared to the previously reported values for the best planar EL devices. Using a reference dye, we estimate the EL quantum efficiency to be ∼1% at low current density limit, which is of the same order of magnitude as photoluminescence quantum yield at the equivalent excitation rate. Our observations reveal that the efficiency of our devices is not limited by carrier-to-exciton conversion efficiency but by the inherent exciton-to-photon yield of the material. The device characteristics indicate that the light emission is triggered by injection of hot minority carriers (holes) to n-doped WS2 by Fowler-Nordheim tunneling and that hBN serves as an efficient hole-transport and electron-blocking layer. Our findings offer insight into the intelligent design of van der Waals heterostructures and avenues for realizing efficient excitonic devices.


Concatenation of the Moving Window Technique for Auditory-Perceptual Analysis of Voice Quality.
The purpose of this study is to develop a program to concatenate acoustic vowel segments that were selected with the moving window technique, a previously developed technique used to segment and select the least perturbed segment from a sustained vowel segment. The concatenated acoustic segments were compared with the nonconcatenated, short, individual acoustic segments for their ability to differentiate normal and pathological voices. The concatenation process sometimes created a clicking noise or beat, which was also analyzed to determine any confounding effects. A program was developed to concatenate the moving window segments. Listeners with no previous rating experience were trained and, then, rated 20 normal and 20 pathological voice segments, both concatenated (2 s) and short (0.2 s) for a total of 80 segments. Listeners evaluated these segments on both the Grade, Roughness, Breathiness, Asthenia, and Strain scale (GRBAS; 8 listeners) and the Consensus Auditory-Perceptual Evaluation of Voice (Kempster, Gerratt, Abbott, Barkmeier-Kraemer, & Hillman, 2009) scale (7 listeners). The sensitivity and specificity of these ratings were analyzed using a receiver-operating characteristic curve. To evaluate if there were increases in particular criteria due to the beat, differences between beat and nonbeat ratings were compared using a 2-tailed analysis of variance. Concatenated segments had a higher sensitivity and specificity for distinguishing pathological and normal voices than short segments. Compared with nonbeat segments, the beat had statistically similar increases for all criteria across Consensus Auditory-Perceptual Evaluation of Voice and GRBAS scales, except pitch and loudness. The concatenated moving window method showed improved sensitivity and specificity for detecting voice disorders using auditory-perceptual analysis, compared with the short moving window segment. It is a helpful tool for perceptual analytic protocols, allowing for voice evaluation using standardized and automated voice-segmenting procedures. https://doi.org/10.23641/asha.7100951.


Trial Validates Biosimilar for Trastuzumab.
Preliminary data from the phase III Heritage trial suggest that a biosimilar to trastuzumab, MYL-14010, is just as safe and effective as its brand-name equivalent for women with HER2-positive advanced breast cancer. The findings, presented during the annual meeting of the American Society of Clinical Oncology in June, may pave the way for the first FDA-approved biosimilar for cancer.


Radiolabeled neurotensin analog, 99mTc-NT-XI, evaluated in ductal pancreatic adenocarcinoma patients.
The study aim was to assess the safety, biodistribution, tissue kinetics, and tumor uptake of the (99m)Tc-labeled neurotensin (NT) analog NT-XI. Four patients presenting ductal pancreatic adenocarcinoma were studied with (99m)Tc-NT-XI. Patients were followed by scintigraphy up to 4 h and by continued blood and urinary sampling until surgery 18-22 h after injection. Surgical tissue samples were analyzed for radioactivity uptake and NT receptor expression. No side effects were observed on injection of (99m)Tc-NT-XI. Blood biologic half-lives alpha and beta were 35 min (range, 17-62 min) and 230 min (range, 107-383 min), respectively. Repeated whole-body scintigraphy performed in 2 patients showed a single exponential decrease of whole-body activity with half-lives of 101 and 232 min. Tracer elimination was mainly renal, with 92% and 98% of activity counted in urine in the first 20 h. Kidney, liver, spleen, and bone marrow activity uptake was observed in all patients. Tumor was not visualized in the first 3 patients but could be localized by tomoscintigraphy in the pancreas head region of patient 4. In vitro tissue analysis showed high expression of NT receptor in the tumor of patient 4, correlated with the highest tumor radioactivity uptake and the highest tumor-to-fat radioactivity ratio. In vitro receptor expression was also positive in a second patient having a tumor characterized by very low cellularity; however, the remaining 2 tumors lacked NT receptor expression. Injection of (99m)Tc-NT-XI was well tolerated. The in vivo tumor uptake appeared specific as it was observed in the 1 patient with a pancreatic tumor that expressed high amounts of NT receptor. The results are compatible with preclinical animal results and in favor of further development of radiolabeled NT analogs for diagnosis or therapy of cancer.


Novel dehydrins lacking complete K-segments in Pinaceae. The exception rather than the rule.
Dehydrins are thought to play an essential role in the plant response, acclimation and tolerance to different abiotic stresses, such as cold and drought. These proteins contain conserved and repeated segments in their amino acid sequence, used for their classification. Thus, dehydrins from angiosperms present different repetitions of the segments Y, S, and K, while gymnosperm dehydrins show A, E, S, and K segments. The only fragment present in all the dehydrins described to date is the K-segment. Different works suggest the K-segment is involved in key protective functions during dehydration stress, mainly stabilizing membranes. In this work, we describe for the first time two Pinus pinaster proteins with truncated K-segments and a third one completely lacking K-segments, but whose sequence homology leads us to consider them still as dehydrins. qRT-PCR expression analysis show a significant induction of these dehydrins during a severe and prolonged drought stress. By in silico analysis we confirmed the presence of these dehydrins in other Pinaceae species, breaking the convention regarding the compulsory presence of K-segments in these proteins. The way of action of these unusual dehydrins remains unrevealed.


Helicobacter pylori induces inflammation in mouse urinary bladder and pelvis.
Helicobacter pylori was transurethrally inoculated into the mouse urinary tract. The organism established infection and induced inflammation in the urinary bladder and pelvis. During the infection, urinary pH was elevated, probably due to the production of NH3 by bacterial urease. H. pylori was recovered from the urinary bladder, kidney and urine of the infected mice. Histopathologically, severe neutrophil infiltration was observed in the mucosal layer of both organs. H. pylori was detected on the surface of the epithelial cells. These results indicate that low pH and bacterial flora were not essential factors in establishing the mucosal infection with H. pylori. This experimental system is useful to investigate the pathogenicity of H. pylori in mucosal organs.


Dichlorido[bis-(2-ethyl-5-methyl-1H-imidazol-4-yl-κN)methane]-cobalt(II) monohydrate.
In the title compound, [CoCl(2)(C(13)H(20)N(4))]·H(2)O, the Co(II) atom lies on a mirror plane and is four-coordinated by two N atoms of the imidazole ligand and two Cl atoms in a distorted tetra-hedral arrangement. The water mol-ecule participates in the formation of hydrogen bonds, resulting in a three dimensional network involving the Cl atoms and the NH groups. The terminal C atom of the ethyl group is disordered over two sites of equal occupancy.


Naturally occurring low affinity peptide/MHC class I ligands can mediate negative selection and T cell activation.
The affinity/avidity model for T cell development postulates that ligands with high affinity for the TCR are efficient in negative selection, whereas those with lower affinity/avidity favor positive selection. Using the 2C TCR transgenic model, we evaluated the efficacy of ligands with widely differing affinity for the TCR (3 x 10(3) to 2 x 10(6) M(-1)) in mediating thymocyte deletion. The relative affinities of the 2C TCR for the p2Ca/Ld, dEV-8/Kb, p2Ca-A3/Ld, and p2Ca/Kb ligands are approximately 1000:50:10:1, respectively. Here we show, using an in vitro assay, that the deletion of 2C CD4+ CD8+ thymocytes is mediated not only by p2Ca/Ld, but also by the lower affinity ligands dEV-8/Kb, p2Ca-A3/Ld, and p2Ca/Kb, albeit at relatively higher peptide concentrations. Deletion mediated by low affinity ligands required CD8, whereas high affinity ligand-mediated deletion was CD8 independent. The p2Ca/Kb and dEV-8/Kb ligands are naturally occurring in H-2b mice, and others have shown that p2Ca/Kb can induce the maturation of CD4- CD8+ 2C-TCR(high) thymocytes in fetal thymic organ culture. In this study we showed that in addition to deletion, the p2Ca/Kb and dEV-8/Kb ligands, in the presence of exogenous IL-2, induced mature 2C T cell proliferation, albeit at a lower level than that induced by the high affinity p2Ca/Ld ligand. Thus, the same low affinity ligands that can effect negative selection and, in the case of p2Ca/Kb, the maturation of CD8 single-positive thymocytes can also induce the activation of mature CD8 T cells.


Neural measures associated with configural threat acquisition.
Contextual threat learning reflects two often competing processes: configural and elemental learning. Configural threat learning is a hippocampal-dependent process of forming a conjunctive representation of a context through binding of several multi-modal elements. In contrast, elemental threat-learning is governed by the amygdala and involves forming associative relationships between individual features within the context. Contextual learning tasks in humans however, rarely probe if a learned fear response is truly due to configural learning vs. simple elemental associations. The aim of the current study was to probe both constructs separately to enable a more refined interpretation of configural vs. elemental threat learning performance and mediating circuits. Subjects (n = 25) performed both a novel feature-identical contextual threat conditioning task and a discrete cue threat acquisition task while undergoing functional magnetic resonance imaging. Results demonstrated increased hippocampus activity for the threat configuration compared to the safe configuration. This pattern was not observed in the amygdala. In contrast, elemental threat learning was associated with increased amygdala, but not hippocampus activity. Whole-brain analyses revealed that both configural and elemental threat acquisition share neural circuitry related to fear expression. These results provide support for the importance of the hippocampus specifically in configural threat acquisition and fear expression.


A cell-based PDE4 assay in 1536-well plate format for high-throughput screening.
The cyclic nucleotide phosphodiesterases (PDEs) are intracellular enzymes that catalyze the hydrolysis of 3,'5'-cyclic nucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), to their corresponding 5'nucleotide monophosphates. These enzymes play an important role in controlling cellular concentrations of cyclic nucleotides and thus regulate a variety of cellular signaling events. PDEs are emerging as drug targets for several diseases, including asthma, cardiovascular disease, attention-deficit hyperactivity disorder, Parkinson's disease, and Alzheimer's disease. Although biochemical assays with purified recombinant PDE enzymes and cAMP or cGMP substrate are commonly used for compound screening, cell-based assays would provide a better assessment of compound activity in a more physiological context. The authors report the development and validation of a new cell-based PDE4 assay using a constitutively active G-protein-coupled receptor as a driving force for cAMP production and a cyclic nucleotide-gated cation channel as a biosensor in 1536-well plates.


Anharmonic Theoretical Vibrational Spectroscopy of Polypeptides.
Because of the size of polypeptides and proteins, the quantum-chemical prediction of their vibrational spectra presents an exceptionally challenging task. Here, we address one of these challenges, namely, the inclusion of anharmonicities. By performing the expansion of the potential energy surface in localized-mode coordinates instead of the normal-mode coordinates, it becomes possible to calculate anharmonic vibrational spectra of polypeptides efficiently and reliably. We apply this approach to calculate the infrared, Raman, and Raman optical activity spectra of helical alanine polypeptides consisting of up to 20 amino acids. We find that while anharmonicities do not alter the band shapes, simple scaling procedures cannot account for the different shifts found for the individual bands. This closes an important gap in theoretical vibrational spectroscopy by making it possible to quantify the anharmonic contributions and opens the door to a first-principles calculation of multidimensional vibrational spectra.


Time-till-breakdown and scalp electrical potential maps of long-range apparent motion.
A series of psychophysical and electrophysiological experiments is reported using the apparent motion (AM) breakdown effect. Breakdown describes an effect in AM in which, during continuous viewing, the percept of smooth of a single stimulus alternates with the percept of two discrete alternating stimuli. Visual evoked potentials (VEPs) were recorded during periods of motion or breakdown ("nonmotion") in horizontal and vertical displays. VEPs were compared with synthetic VEPs ("composite-flash") produced by adding VEPs to each element of the display recorded in isolation. Subtraction of VEPs was used in an attempt to compare the electrical responses with the processing of information relating to the form of the stimulus, subthreshold motion processing, and suprathreshold motion processing. The results, presented as scalp electrical potential distribution maps, were interpreted as consistent with a central adaptation process underlying the breakdown effect. The results also indicated that the hemispheric asymmetries in AM VEPs described by Manning, Finlay, and Fenelon (1988) were most likely due to the position of the stimuli in the visual field, rather than as a lateralization of motion processes per se. The results also provided evidence that the subthreshold and suprathreshold motion responses to the display were the product of different populations of motion units.


Optimization of the 2-arylquinazoline-4(3H)one scaffold for a selective and potent antitrypanosomal agent: modulation of the mechanism of action through chemical functionalization.
We sought to identify a potent and selective antitrypanosomal agent through modulation of the mechanism of action of a 2-arylquinazoline scaffold as an antitrypanosomal agent via chemical functionalization at the 4-position. We wished to use the: (i) susceptibility of trypanosomatids towards nitric oxide (NO) and reactive oxygen species (ROS); (ii) capacity of the 4-substituted quinazoline system to act as an antifolate agent. Three quinazolin-based moieties that differed from each other by having at the 4-position key pharmacophores targeting the induction of NO and ROS production were evaluated in vitro against Leishmania infantum and Trypanosoma cruzi parasites and their modes of action were explored. Replacement of an oxygen moiety at the 4-position of the antifolate 2-arylquinazolin-4(3H)one by hydrazinyl and 5-nitrofuryl-hydrazinyl pharmacophores enhanced antitrypanosomatid activity significantly due to promotion of an additional mechanism beyond the antifolate response such as NO or ROS production, respectively. Among the three types of chemical functionalization, the 5-nitrofuryl-hydrazinyl moiety generated the most potent compounds. Compound 3b was a potential candidate thanks to its sub-micromolar response against the promastigotes/amastigotes of L. infantum and epimastigote of T. cruzi, moderate toxicity on macrophages (J774.1), good selectivity index (∼15.1-17.6) and, importantly, non-mutagenic effects. 2-Arylquinazoline could be an attractive platform to design new anti-trypanosomatid agents with the use of key pharmacophores.


Pseudo-Jahn-Teller origin of the low barrier hydrogen bond in N(2)H(7) (+).
The microscopic origin and quantum effects of the low barrier hydrogen bond (LBHB) in the proton-bound ammonia dimer cation N(2)H(7) (+) were studied by means of ab initio and density-functional theory (DFT) methods. These results were analyzed in the framework of vibronic theory and compared to those obtained for the Zundel cation H(5)O(2) (+). All geometry optimizations carried out using wavefunction-based methods [Hartree-Fock, second and fourth order Moller-Plesset theory (MP2 and MP4), and quadratic configuration interaction with singles and doubles excitations (QCISD)] lead to an asymmetrical H(3)N-H(+)cdots, three dots, centeredNH(3) conformation (C(3v) symmetry) with a small energy barrier (1.26 kcalmol in MP4 and QCISD calculations) between both equivalent minima. The value of this barrier is underestimated in DFT calculations particularly at the local density approximation level where geometry optimization leads to a symmetric H(3)Ncdots, three dots, centeredH(+)cdots, three dots, centeredNH(3) structure (D(3d) point group). The instability of the symmetric D(3d) structure is shown to originate from the pseudo-Jahn-Teller mixing of the electronic (1)A(1g) ground state with five low lying excited states of A(2u) symmetry through the asymmetric alpha(2u) vibrational mode. A molecular orbital study of the pseudo-Jahn-Teller coupling has allowed us to discuss the origin of the proton displacement and the LBHB formation in terms of the polarization of the NH(3) molecules and the transfer of electronic charge between the proton and the NH(3) units (rebonding). The parallel study of the H(5)O(2) (+) cation, which presents a symmetric single-well structure, allows us to analyze why these similar molecules behave differently with respect to proton transfer. From the vibronic analysis, a unified view of the Rudle-Pimentel three-center four-electron and charge transfer models of LBHBs is given. Finally, the large difference in the N-N distance in the D(3d) and C(3v) configurations of N(2)H(7) (+) indicates a large anharmonic coupling between alpha(2u)-alpha(1g) modes along the proton-transfer dynamics. This issue was explored by solving numerically the vibrational Schrodinger equation corresponding to the bidimensional E[Q(alpha(2u)),Q(alpha(1g))] energy surface calculated at the MP46-311++G(**) level of theory.


[Effects of mild moxibustion on contents of blood lipoids and serum NO in hyperlipidemia rats].
To observe the effect mechanisms of mild moxibustion in treatment of hyperlipidemia. Sixty SD rats were randomly divided into a normal group, a model group, a moxibustion group, an acupuncture group and a medication group, 12 rats in each group. The hyperlipidemia model was established by intro-gastric administration of fat emulsion for 4 weeks in the later four groups, and 0.9% sodium chloride was given in the normal group. Treatments started when hyperlipidemia model was sullessfully established. No treatment was given in the normal group and the model group. The acupuncture group and the moxibustion group were treated with acupuncture and moxibustion at Zusanli (ST 36) and Shenque (CV 8), respectively, once a day. The medication group was treated with introgastric administration of lovastatin (10 mg/kg), once a day. The model group, acupuncture group, moxibustion group and medication group were treated with continuing introgastric administration during the 4-week treatment. Four blood lipoids items were detected by biochemical colorimetry, and the contents of serum NO were measured by nitrate reductase method. Compared with the model group, the contents of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and NO in the moxibustion group, acupuncture group and medication group were decreased (P < 0.01, P < 0.001), mean-while, high-density lipoprotein cholesterol (HDL-C) showed a increasing trend without statistical significance. The moxibustion group was better than the medication group at the effect in decreasing the contents of TC, LDL-C and NO. NO had positive correlation with TC and LDL-C in the moxibustion group (P < 0.05, P < 0.01), while NO had negative correlation with TC and LDL-C in the medication group (both P < 0.01). Mild moxibustion has a favorable regulative action on blood lipoids and serum NO in hyperlipidemia rats. Mild moxibustion can play a role in anti-vascular injury, anti-inflammation and prevention of atherosclerosis by lowering the serum NO in rats.


Extracorporeal shock wave therapy for injection site panniculitis in multiple sclerosis patients.
Painful cutaneous injection site reactions may hamper treatment with interferon β (IFN-β) and glatiramer acetate (GA) in multiple sclerosis (MS) patients. To maintain therapy adherence, efficient therapeutic modalities for these subcutaneous inflammatory lesions are urgently needed. We tested the application of local extracorporeal shock wave therapy (ESWT). We applied 5 sessions of ESWT to 8 patients suffering from MS who had developed painful panniculitis at the injection sites of either IFN-β or GA. Clinical outcomes, i.e. pain reduction and regression of induration, were assessed 3 and 6 months after completion of the ESWT using a visual analogue score. All patients showed both significant pain reduction and reduction of the skin induration in the treated lesions, while in untreated control lesions there was no improvement. ESWT proved to be a non-invasive, safe and efficient physical treatment modality for injection-induced painful cutaneous side effects of disease-modifying drugs in MS.


Localized electrochemical impedance spectroscopy: visualization of spatial distributions of the key parameters describing solid/liquid interfaces.
Acquisition of localized electrochemical impedance spectra as a function of spatial coordinates combined with novel approaches of data analysis brings a key for visualization of two-dimensional distributions of important parameters describing solid/liquid interfaces. They include the capacitance of the electric double layer, the resistance of the interfacial charge transfer, capacitances of adsorption, or other parameters depending on the properties of the system. Additionally, the proposed approach eliminates many common methodological problems of localized electrochemical impedance microscopies related to the frequency dependence of the actual pictures and difficulties with raw data interpretation. Thus, it offers a unique insight into the localized processes at the interface which is not possible to achieve using classical techniques.


A Novel Retinoblastoma Protein (RB) E3 Ubiquitin Ligase (NRBE3) Promotes RB Degradation and Is Transcriptionally Regulated by E2F1 Transcription Factor.
Retinoblastoma protein (RB) plays critical roles in tumor suppression and is degraded through the proteasomal pathway. However, E3 ubiquitin ligases responsible for proteasome-mediated degradation of RB are largely unknown. Here we characterize a novel RB E3 ubiquitin ligase (NRBE3) that binds RB and promotes RB degradation. NRBE3 contains an LXCXE motif and bound RB in vitro. NRBE3 interacted with RB in cells when proteasome activity was inhibited. NRBE3 promoted RB ubiquitination and degradation via the ubiquitin-proteasome pathway. Importantly, purified NRBE3 ubiquitinated recombinant RB in vitro, and a U-box was identified as essential for its E3 activity. Surprisingly, NRBE3 was transcriptionally activated by E2F1/DP1. Consequently, NRBE3 affected the cell cycle by promoting G1/S transition. Moreover, NRBE3 was up-regulated in breast cancer tissues. Taken together, we identified NRBE3 as a novel ubiquitin E3 ligase for RB that might play a role as a potential oncoprotein in human cancers.


Benefits of the Treatment and Education of Autistic and Communication Handicapped Children (TEACCH) programme as compared with a non-specific approach.
Two educational treatments were compared, the Treatment and Education of Autistic and Communication Handicapped Children (TEACCH) programme and the integration programme for individuals with disabilities. Two groups of eight subjects were matched by gender, chronological and mental age, and nosographic diagnosis (i.e. autism associated with severe intellectual disability, DSM-IV criteria and Childhood Autism Rating Scale scored. The TEACCH programme was applied to the experimental group, while the control group was integrated in regular schools with a support teacher. The Psycho-Educational Profile-Revised and the Vineland Adaptive Behaviour Scale were administered twice with a one-year interval between assessments. The scores of the experimental group increased more than the control group scores. Statistically significant differences were obtained in both groups because of the differences in the two approaches.


Choroidal and cutaneous metastasis from urothelial carcinoma of the bladder after radical cystectomy: a case report and literature review.
Bladder cancer is the second most common genitourinary malignancy and has variable metastatic potential; however, choroidal and cutaneous metastases are extremely rare. Generally, a patient with these uncommon metastases has a very poor prognosis. We present a bladder cancer patient with a visual disorder in the right eye and multiple nodules on head and lower abdomen that developed 17 months after a radical cystectomy. These symptoms were determined to be caused by choroidal and cutaneous metastasis of bladder cancer. Although two cycles of combination chemotherapy were performed, the patient died 5 months after diagnosis of multiple metastases.


Molt-dependent transcriptomic analysis of cement proteins in the barnacle Amphibalanus amphitrite.
A complete understanding of barnacle adhesion remains elusive as the process occurs within and beneath the confines of a rigid calcified shell. Barnacle cement is mainly proteinaceous and several individual proteins have been identified in the hardened cement at the barnacle-substrate interface. Little is known about the molt- and tissue-specific expression of cement protein genes but could offer valuable insight into the complex multi-step processes of barnacle growth and adhesion. The main body and sub-mantle tissue of the barnacle Amphibalanus amphitrite (basionym Balanus amphitrite) were collected in pre- and post-molt stages. RNA-seq technology was used to analyze the transcriptome for differential gene expression at these two stages and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) was used to analyze the protein content of barnacle secretions. We report on the transcriptomic analysis of barnacle cement gland tissue in pre- and post-molt growth stages and proteomic investigation of barnacle secretions. While no significant difference was found in the expression of cement proteins genes at pre- and post-molting stages, expression levels were highly elevated in the sub-mantle tissue (where the cement glands are located) compared to the main barnacle body. We report the discovery of a novel 114kD cement protein, which is identified in material secreted onto various surfaces by adult barnacles and with the encoding gene highly expressed in the sub-mantle tissue. Further differential gene expression analysis of the sub-mantle tissue samples reveals a limited number of genes highly expressed in pre-molt samples with a range of functions including cuticular development, biominerialization, and proteolytic activity. The expression of cement protein genes appears to remain constant through the molt cycle and is largely confined to the sub-mantle tissue. Our results reveal a novel and potentially prominent protein to the mix of cement-related components in A. amphitrite. Despite the lack of a complete genome, sample collection allowed for extended transcriptomic analysis of pre- and post-molt barnacle samples and identified a number of highly-expressed genes. Our results highlight the complexities of this sessile marine organism as it grows via molt cycles and increases the area over which it exhibits robust adhesion to its substrate.


Tolerance of high altitude acclimatized rats to blood loss at sea level.
After acclimatization to high altitude, the sea level haemorrhagic tolerance of rats was measured by determining the bleeding volume which resulted in death under anaesthesia following cannulation. For each animal this was recorded as a bleeding volume index (BVI), the total volume of blood lost per 100 g of body weight. The mean BVI of altitude acclimatized rats was greater than that for non-acclimatized rats (P less than 0.001), showing that chronic exposure to altitude enabled the animals to tolerate more severe blood loss. Evidence is presented which suggests that the increased haemorrhagic tolerance resulted, in part, from an increased initial blood volume and an increased ability for arterial blood pressure regulation during haemorrhage.


Prevalence and determinants of erectile dysfunction among diabetic patients attending in hospitals of central and northwestern zone of Tigray, northern Ethiopia: a cross-sectional study.
The prevalence of erectile dysfunction among diabetic men varies between 35-90%. Although erectile dysfunction is widespread among men with diabetes, the condition often remains undiagnosed and demands appropriate assessment and prompt treatment. Erectile dysfunction can affect all aspects of a patient's life including physical, emotional, social, sexual, and relationships. The main aim of this study is to determine the prevalence and determinants of erectile dysfunction among diabetic patients attending hospitals in the Central and Northwest zone of Tigray, Ethiopia. A hospital based cross-sectional study was conducted on 249 male diabetic patients attending five hospitals in the Central and Northwestern Zone of Tigray, Ethiopia using systematic random sampling. The data was collected from January 1 - February 30, 2016 and was entered and analyzed using SPSS version 20. Correlation and multivariate logistic regression was employed to test associations between independent and outcome variables. The mean age of study participants was 43.39 years and the mean duration of diabetes diagnosis was 6.22 years. The overall prevalence of erectile dysfunction was 69.9%, with 32.9% suffering from mild, 31.7% moderate, and 5.2% severe erectile dysfunction. Multivariate logistic regression revealed that erective dysfunction was significantly predicted by old age (Adjusted Odds Ratio [AOR] =15.013, CI:3.212-70.166), longer duration of diabetes (AOR = 3.77, CI:1.291-11.051), and lower monthly income (AOR = 0.285, CI:0.132-0.615). No association was found with body mass index, co-morbidity, glycemic control, and alcohol consumption. The prevalence of erective dysfunction in this study population was very high. Age, income, and duration of diabetes were the independent predictors of erectile dysfunction. Nearly all of the patients in the sample (97%) had not been screened or treated for erectile dysfunction. Assessment and management of erectile dysfunction in the diabetic clinic should be part of routine medical care during follow-up visits with diabetic patients. Healthcare providers should put an emphasis on screening and treating older patients and those who had a diabetes diagnosis for a longer duration.


Intratumoral radiofrequency hyperthermia-enhanced chemotherapy of liposomal doxorubicin on hepatocellular carcinoma.
To investigate the possibility of using radiofrequency hyperthermia (RFH) to enhance intratumoral therapeutic effect of liposomal doxorubicin on hepatocellular carcinoma (HCC) via an interventional molecular imaging approach. For both in-vitro confirmation and in-vivo validation, Luciferase/mCherry-labeled human HCC cells (HepG2) and mice subcutaneous hepatic cancer xenografts were treated by: (i) combination therapy of liposomal doxorubicin plus RFH at 42°C; (ii) liposomal doxorubicin alone; (iii) RFH at 42°C alone; (iv) phosphate buffered saline (PBS) as a control. For in-vitro confirmation, MTS assay, confocal microscopy, optical imaging and flow cytometry were used to evaluate and compare cell viabilities and apoptosis among different treatment groups. For in vivo validation, liposomal doxorubicin was directly injected into the tumor and RFH was performed subsequently under ultrasound imaging guidance. Changes of tumor sizes were quantified using ultrasound imaging and bioluminescence signal intensities after treatments were measured by optical imaging over 14 days, which were correlated with subsequent histology analysis. Of in vitro experiments, MTS assay demonstrated the lowest cell proliferation in combination therapy group compared with the other three groups (25.0 ± 5.6% vs 49.7 ± 5.2% vs 94.2 ± 3.9% vs 100%, respectively, P < 0.001). Flow cytometry showed the highest percentage of early apoptotic HepG2 cells in combination therapy compared to the other three groups (37.9 ± 3.2% vs 32.2 ± 1.7% vs 2.9 ± 1.7% vs 1.8 ± 0.7%, respectively, P < 0.001). Of in vivo experiments, optical imaging demonstrated a significantly decreased bioluminescence signal intensities in the combination therapy group, compared with the other three groups (0.53 ± 0.10 VS 1.4 ± 0.5 VS 2.8 ± 0.8 VS 3.0 ± 0.3, P < 0.05). Ultrasound images showed the smallest tumor volumes of the combination therapy group, in comparison to other control groups (0.7 ± 0.1 VS 1.8 ± 0.4 VS 3.0 ± 0.8 VS 3.3 ± 0.3, P < 0.05). Both histologic correlation confirmed imaging findings. RFH can enhance intratumoral therapy with liposomal doxorubicin for HCC, which is effectively monitored by ultrasound imaging and optical imaging techniques. This concept may provide new avenues for eradicating the residual tumor cells when combining RFA with interventional molecular imaging guided direct intratumoral chemotherapy of HCC.


The initial neurosurgical interventions for the treatment of posthaemorrhagic hydrocephalus in preterm infants: A focused review.
Post-haemorrhagic hydrocephalus (PHH), a potential consequence of grade II-IV germinal matrix haemorrhage, remains a significant problem in premature infants with long-term neurodevelopmental disabilities and high mortality rates. Early ventriculoperitoneal shunt (VPS) insertion is associated with a high failure rate and many complications; hence, temporising measures are always instituted until the infant is mature (age and/or weight) enough. We have reviewed the recently available literature on the usefulness and complications of the initial measures used in the treatment of PHH; particularly, focusing on serial cerebrospinal fluid (CSF) tapping, external ventricular drainage (EVD), ventriculosubgaleal shunts (VSG), ventricular access devices (VADs), endoscopic third ventriculostomy (ETV) with and without coagulation of the choroid plexus. Randomised controlled trials (RCTs) have failed to demonstrate a significant effect of serial lumbar punctures on the rates of morbidity, mortality or conversion to permanent VPS in the treatment of PHH. Retrospective studies, mostly with small patients' numbers, provide not only a considerable controversy regarding EVD, VSG, VADs and ETV usefulness in the management of PHH but also variable rates on their complications. None of these variables have, however, been tested using RCTs. There is no level-one evidence to support the superiority of any of the currently available temporising measures in the initial treatment of PHH over others. The need for such rigorous studies remains largely unmet. We feel that a UK multi-centre-RCT is paramount to provide neurosurgeons with the evidence needed to choose the best initial approach for PPH treatment, yet with minimal complications' rate.